Allergies have been the bane of human existence since the beginning of human history. Those individuals afflicted with allergies suffer with continual or repeated bouts of sinusitis, rhinitis, itchy watery eyes, nose and mouth, and allergic asthma which may be so severe as to cause hospitalization. The most dangerous human allergic response is anaphylaxis, which will cause death without medical intervention.
Pharmaceuticals to alleviate many of the less severe symptoms have been developed such as oral administration of antihistamines, inhalers for asthma, and portable injection kits containing adrenaline to suppress anaphylactic shock until medical help can be reached. However, these pharmaceuticals do nothing more than mask the symptoms caused by histamine release, the end result of the human immune response which begins when the offending allergen enters the body. Furthermore, many of the more powerful antihistamine drugs have undesirable side effects such as excessive dryness of the mucosa or drowsiness.
Over the past several decades a therapy involving desensitization of humans has been developed. Desensitation therapy involves repeated injections with increasing dosages of a crude allergen extract of the offending allergen. Although treatment with allergen extracts has been proven somewhat effective in the clinic for alleviating allergen-related symptoms, and is a common therapy used most widely in allergy clinics today, the mechanism of desensitization remains unclear. Furthermore, desensitization therapy must be undertaken with extreme caution as the side effects may be significant or even fatal (i.e. anaphylaxis). Thus, it is necessary for the patient to undergo multiple injections of incrementally larger dosages of the crude extract, and remain under medical observation for one or more hours every time an injection is given. In addition, it is often necessary for an allergic patient to receive treatment until maintenance dose is reached which usually requires treatment injection once a week for six to twelve months and at intervals of four to six weeks thereafter. Thus, this treatment is very time intensive, inconvenient and not without side effects or danger for the patient.
In an attempt to make desensitization immunotherapy more effective and safer, several investigators have attempted to develop modified allergens with the intention of effecting the immunological events which occur during immunotherapy (i.e. to increase blocking IgG antibodies or decrease the number of allergen specific IgE antibodies). Such modifications include preparing and testing: urea-denatured allergens, Ishizaka et al, E. J. Immunol. 114:100-115 (1975); allergoids created by formalin treatment of allergens; Norman et al., J Allergy Clin Immunol, 70:248-260 (1982); allergens bound to tolerogens such as D-glutamic acid-D-lysine, Katz D., Immunology, 41:1-24 (1980);or polyethyleneglycol, Sehon et al, J Allergy Clin Immunol 64:242-250 (1979); and glutaraldehyde-polymerized allergens, Metzger et al. N Engl J Med 295:1160-1164 (1976).
Michael et al., U.S. Pat. No. 4,338,297, disclose a polypeptide active pollen immunosuppressant prepared by proteolytic enzyme digestion of pollen antigen and purified by reaction with antipollen antibody potentially for use as a therapeutic in desensitization. Later, the same group published experiments indicating that it was possible to suppress the immune response in mice to protein antigens such as bovine serum and honey bee venom phospholipase A2 by treatment with fragments derived by enzymatic digestion (Michael et al., J Clin Immunol, 75:200(abstr) (1985), and Ferguson et al., Cell Immunol, 78:1-12 (1983)), and in addition found that fragmenting allergenic proteins of short ragweed pollen by peptic digestion and administering digestion products in the molecular weight range of 5-15 kD either prior to, or after intraperitoneal immunization with a ragweed preparation resulted in suppression of the immune response (Michael et al., Clin Exp Allergy, 20:669-674 (1990)). According to Michael et al., it was believed that the suppression of the immune response to the ragweed preparation involved T cells, and that the fragments of the peptic digest were capable of stimulating T cells that regulate immunosuppression.
In addition, the same group of investigators tested a composition comprising peptic fragments of short ragweed for clinical effectiveness in humans, (Litwin et al. Clin Exp Allergy 21:457-465 (1991)). In this study, three groups of ragweed hay fever patients were placed on pre-seasonal immunotherapy. One group received a conventional ragweed preparation that had been enriched for ragweed antigen (Amb a I) designated Pool 2. The proteins in Pool 2 contained about 26% Amb a I. Pool 2 was enzymatically digested and a fraction containing proteins in the 10kD range or less was used as the peptic fragment composition and designated fSRW. The third group was given a placebo. Although the results indicated that the groups given either Pool 2 or fSRW had significantly reduced symptom-medication scores compared with the placebo-treatment group, the differences between the fSRW treatment and the Pool 2 treatment were not significant. Thus, the fSRW peptic digest composition did not totally achieve its goal of providing significant efficacy or convenience over a conventional immunotherapy composition comprising a crude extract of the allergen to which the individual is sensitive, and has not been thus far approved for use in the United States or is such a peptic composition presently the subject of a clinical study in the United States.
Furthermore, the use of a composition comprising peptic fragments of a protein allergen such as that described by Litwin et al. has serious drawbacks. For example the protein extract (Pool 2) which was digested to produce the fSRW peptide composition was enriched for the desired Amb a I protein to only 26% and any number of other proteins and contaminants were likely present in the Pool 2 composition and were carried over to the fSRW digest. According to Litwin et al., the precise Amb a I content in fSRW could not be determined because components of the fSRW did not remain in solution. Thus the fSRW may have contained undesirable proteins which may have adverse effects on the patients being treated, and therefore, provides no advantage over the use of a conventional crude extract, and moreover, may have many of the same disadvantages associated with classic immunotherapy. In addition, the enzymatic digest of a crude protein does not consistently produce the same composition of peptides every time. Therefore, it would be almost impossible to produce consistent, precisely-defined, highly purified compositions of peptides for use as a pharmaceutical for human treatment as is required by most regulatory agencies throughout the world using a composition of enzymatically digested proteins, similar to that of fSRW described by Litwin et al.
In addition, similar to allergy, autoimmnune diseases such as Type I diabetes, multiple sclerosis, and rheumatoid artritis are generally accepted as being the result of an antigen specific T cell mediated response against an antigen which in the case of autoimmune disease, is the body""s own tissue. Therefore, it is believed an approach to treating autoimmune disease which is conceptually similar to that for treating allergies would be appropriate. For example, WO 88/10120, WO 91/08760, WO 92/06704, WO 93/21222, and WO 94/07520, describe oral or enteral administration of whole autoantigens, or fragments thereof such as mylein basic protein, (MBP a presumed autoantigen in multiple sclerosis), insulin for the treatment of diabetes, or collagen for the treatment of rheumatoid arthritis. For many of the reasons described above, there are limits to the clinical applicability of oral, enteral or aerosol administration of autoantigens such as an inability to characterize the active component of a thereapeutic composition once introduced in the stomach due to subsequent enzymatic degradation in the stomach. Thus, predictable and reproducible therapeutic effects may be difficult to achieve using these methods, not to mention the potential for adverse side effects as a result of the body""s further processing of the therapeutic which may not be predictable.
The present invention overcomes the drawbacks described above and provides methods for treating allergies and other diseases associated with an immune response by the human to a protein antigen (i.e. autoimmune diseases), using precisely-defined, highly purified, preparations comprising at least one peptide having a defined sequence of amino acid residues which comprises at least one T cell epitope of the protein antigen, administered in non-immunogenic form. Preferred, compositions and methods of treating humans in accordance with the present invention have been tested in the clinic and have been shown to be successful. The ramifications of these successful clinical trials are expected to change the face of allergy immunotherapy forever, as well as change the course of treatment of autoimmune diseases and other areas relating to human disease conditions associated with the immune response.
The present invention provides therapeutic compositions and methods for treating disease conditions in humans associated with an antigen specific immune response by the human to an antigen such as a protein antigen (i.e. allergy and autoimmune diseases). Therapeutic compositions of the invention are precisely-defined, highly purified reproducible preparations which are suitable for human therapy. Preferred compositions of the invention comprise at least one isolated, purified peptide, free from all other polypeptides or contaminants, the peptide having a defined sequence of amino acid residues which comprise at least one T cell epitope of an antigen of interest. A therapeutic composition of the invention is capable of down regulating an antigen specific immune response to an antigen of interest in a population of humans subject to the antigen specific immune response such that disease symptoms are reduced or eliminated, and/or the onset or progression of disease symptoms is prevented or slowed.
Compositions and methods of the invention may be used to treat sensitivity to protein allergens in humans such as allergies to ragweed, grasses, trees, house dust mite (dust), cats, dogs and other animals, and any other airborne or contact allergens. Compositions and methods of the invention may also be used to treat autoimmune disease such as rheumatoid arthritis, diabetes, myasthenia gravis, Grave""s disease, Good Pasture""s syndrome, thyroiditis and multiple sclerosis.